Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:15][C@@H:14]([OH:16])[CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH3:50][NH:51][CH2:52][CH2:53][CH2:54][CH2:55][CH:56]=[CH2:57].CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:52]([N:51]([CH3:50])[C:10]([C@@H:9]1[CH2:13][C@@H:14]([OH:16])[CH2:15][N:8]1[C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])=[O:12])[CH2:53][CH2:54][CH2:55][CH:56]=[CH2:57]
Reactant: C=CCCCCNC
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CCCCCN(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a cold solution of cis-N-Boc-4-hydroxy-L-proline (10 g. 1 eq.), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU 15.5 g, 1.12 eq.) and N-methylhex-5-en-1-amine tosylate salt 32a (13.6 g, 1.1 eq.), which was prepared according to Scheme 13 as described herein, in DMF (80 mL) containing DIPEA (29.4 mL, 3.9 eq.) was added dropwise under nitrogen at 0° C. The reaction mixture was stirred overnight at room temperature, and then quenched with water and extracted with diethyl ether. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel to yield compound 48 as a rose powder in 95% yield. 1H NMR (DMSO-d6, 400 MHz): δ (ppm) 1.29-1.3 (m, 9H), 1.33-1.55 (m, 4H), 1.70-1.80 (m, 1H), 1.97-2.12 (m, 3H), 2.77-2.97 (m, 3H), 3.15-3.40 (m, 4H), 4.22 (br s, 1H), 4.50-4.62 (m, 1H), 4.90-5.04 (m, 3H), 5.71-5.83 (m, 1H); MS (ESI+): m/z=327 (MH+).
Reaction SMILES: CO[C:3]1[CH2:4][CH:5]([CH3:11])[CH:6]([CH2:8][CH:9]=[CH2:10])[N:7]=1.[Cl-:12].[NH4+:13]>CO>[ClH:12].[CH3:11][CH:5]1[CH:6]([CH2:8][CH:9]=[CH2:10])[NH:7][C:3](=[NH:13])[CH2:4]1
Reactant: C=CCC1N=C(OC)CC1C
Reactant: [NH4+]
Reactant: [Cl-]
Solvent: CO
Product: C=CCC1NC(=N)CC1C
Product: Cl

Procedure:
The product of EXAMPLE 266 in MeOH is reacted with ammonium chloride by the method of EXAMPLE 27 to generate the title material.
Reaction SMILES: [Cl-:1].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][C:11](=[O:15])[NH:12]2)=[CH:8][CH:7]=1.[C:16](Cl)(=[O:18])[CH3:17]>C(Cl)Cl>[Cl:1][CH2:17][C:16]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:6]=1[F:5])[NH:12][C:11](=[O:15])[CH2:10]2)=[O:18]
Reactant: [Cl-]
Reactant: O=C1Cc2ccc(F)cc2N1
Reactant: CC(=O)Cl
Agent: [Al+3]
Solvent: ClCCl
Product: O=C1Cc2cc(C(=O)CCl)c(F)cc2N1
Temperature: 50 °C

Procedure:
20 mL of DCM are added dropwise under nitrogen to aluminium chloride (31.1 mmol) at 0-5° C. 6-Fluoroindolin-2-one (5.18 mmol) and acetyl chloride (6.73 mmol) are added to the mixture. The reaction mixture is heated at 50° C. overnight. The reaction mixture is cooled to ambient temperature and then poured into an ice bath, and the suspension obtained is filtered and then washed with cold water to yield the title product.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[N+:12]([CH:15]=[C:16](SC)[S:17]([CH3:19])=O)([O-:14])=[O:13].C[O-].[Na+]>C(O)C.CO>[CH3:19][S:17][C:16]1[NH:2][CH:3]=[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:15]=1[N+:12]([O-:14])=[O:13]
Reactant: NCC(=O)c1ccccc1
Reactant: CSC(=C[N+](=O)[O-])S(C)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CSc1[nH]cc(-c2ccccc2)c1[N+](=O)[O-]
Reaction time: 0.17 h
Yield: 60.4 %

Procedure:
α-Aminoacetophenone hydrochloride (6.87 g, 0.040 mol) was mixed with 1-nitro-2-methylthio-2-methylsulphinylethylene (7.25 g, 0.040 mol) in 300 ml dry ethanol and warmed at 60°. Sodium methoxide (from 0.92 g sodium, 0.080 g atom) in methanol (25 ml) was added dropwise, with stirring, over about 10 minutes. After addition, the mixture was stirred at 60° for one hour, and then filtered to give 2-methylthio-3-nitro-4-phenylpyrrole 5.66 g, m.p. 259°-261° dec.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:14][C:15](=[O:23])OC2C=CC=CC=2)[CH:5]=[CH:6][C:7]=1[CH2:8][NH:9][S:10]([CH3:13])(=[O:12])=[O:11].[C:24]1([CH3:42])[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[C:35]([CH2:36][NH2:37])=[CH:34][CH:33]=[C:32]([C:38]([F:41])([F:40])[F:39])[N:31]=2)[CH:25]=1>C(#N)C.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:14][C:15]([NH:37][CH2:36][C:35]2[C:30]([C:26]3[CH:25]=[C:24]([CH3:42])[CH:29]=[CH:28][CH:27]=3)=[N:31][C:32]([C:38]([F:41])([F:39])[F:40])=[CH:33][CH:34]=2)=[O:23])[CH:5]=[CH:6][C:7]=1[CH2:8][NH:9][S:10]([CH3:13])(=[O:11])=[O:12]
Reactant: CS(=O)(=O)NCc1ccc(NC(=O)Oc2ccccc2)cc1F
Reactant: Cc1cccc(-c2nc(C(F)(F)F)ccc2CN)c1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)Nc2ccc(CNS(C)(=O)=O)c(F)c2)c1
Temperature: 50 °C
Reaction time: 15 h
Yield: 71.2 %

Procedure:
To a stirred solution of phenyl 3-fluoro-4-(methylsulfonamidomethyl)-phenylcarbamate (67 mg, 0.198 mmol) and (2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methanamine (53 mg, 0.198 mmol) in acetonitrile were added 4-dimethylaminopyridine (24 mg, 0.198 mmol). The reaction mixture was stirred for 15 h at 50° C. The mixture was dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography. N-(2-Fluoro-4-(3-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)ureido)benzyl)methanesulfonamide (example 27) (72 mg) was obtained as 72% yield.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([OH:3])=[O:2].O.[N+:13]([CH2:16][CH3:17])([O-:15])=[O:14]>C(N)CCC>[C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[C:16]([N+:13]([O-:15])=[O:14])[CH3:17])=[CH:6][CH:5]=1)([OH:3])=[O:2]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CC[N+](=O)[O-]
Solvent: CCCCN
Solvent: O
Product: CC(=Cc1ccc(C(=O)O)cc1)[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A solution of 4-carboxybenzaldehyde (38.44 g) in nitroethane (360 ml) and butylamine (2 ml) was heated at reflux for 2 hours with azeotropic distillation of water using a Dean and Stark apparatus The solution was cooled to room temperature and the resulting solid was collected and recrystallised from isopropanol (250 ml) with hot filtration to give 1-(4-carboxyphenyl)-2-nitropropene (31.57 g) in the form of a yellow crystalline solid, m.p. 212°-214° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][C:6]2[C:9]3[C:14]([NH:15][C:16]4[CH:25]=[CH:24][C:19]5[NH:20][C:21](=[O:23])[S:22][C:18]=5[CH:17]=4)=[N:13][CH:12]=[N:11][C:10]=3[S:26][C:5]=2[CH2:4]1.CN(C)C=O.[C:32](Cl)(=[O:37])[O:33][CH:34]([CH3:36])[CH3:35].C(N(CC)CC)C>O>[O:23]=[C:21]1[NH:20][C:19]2[CH:24]=[CH:25][C:16]([NH:15][C:14]3[C:9]4[C:6]5[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][C:32](=[O:37])[O:33][CH:34]([CH3:36])[CH3:35])[CH2:4][C:5]=5[S:26][C:10]=4[N:11]=[CH:12][N:13]=3)=[CH:17][C:18]=2[S:22]1
Reactant: NCC1CCc2c(sc3ncnc(Nc4ccc5[nH]c(=O)sc5c4)c23)C1
Reactant: CC(C)OC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)OC(=O)NCC1CCc2c(sc3ncnc(Nc4ccc5[nH]c(=O)sc5c4)c23)C1
Yield: 40 %

Procedure:
A mixture comprising 50 mg (130 μmol) (RS)-6-{[7-(aminomethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-yl]amino}-1,3-benzothiazol-2(3H)-one (prepared according to example 20), 5 mL N,N-dimethylforamide, 130 μL isopropyl carbonochloridate (1M in toluene) and 18.2 μL N,N-diethylethanamine was stirred at 23° C. overnight. Water was added, the solvents were removed and the residue purified by chromatography to give 25 mg (40%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[N:16]#[C:17][NH2:18].[N+:19]([O-:22])([OH:21])=[O:20]>C(O)C.O.Cl>[N+:19]([O-:22])([OH:21])=[O:20].[N+:19]([O-:22])([OH:21])=[O:20].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:17]([NH2:18])=[NH:16])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: N#CN
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: O=[N+]([O-])O
Product: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 58.4 %

Procedure:
To a solution of 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (5.08 g, 25.0 mmol) in ethanol (25 mL) was added at 20° C. cyanamide (3.15 g, 75 mmol) dissolved in water (3.2 mL) and then 37% aqueous hydrochloric acid solution (4.9 g, 50 mmol). The solution was heated for 3 h to reflux. Additional cyanamide (2.1 g) in water (2.1 mL) and 37% aq hydrochloric acid solution (2.8 mL) were added and the mixture was heated to reflux for another 2 h. At 20° C. 65% aqueous nitric acid (3.5 mL, 50 mmol) was added. The reaction was stirred for 30 minute at 20° C. and the formed precipitate was filtered off, washed with ethanol and diethyl ether. (Caution: the filtrate may contain the ethyl ester of nitric acid). The solid was dried under reduced pressure at 20° C. to yield the title compound (5.42 g, 58%) as a white solid.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][N:10]([C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])[CH2:9][CH2:8][N:7]1[S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]#[C:32][CH3:33])=[CH:25][CH:24]=1)(=[O:22])=[O:21])=[O:5])C.O.[OH-].[Li+]>C1COCC1.CO.O>[CH2:30]([O:29][C:26]1[CH:25]=[CH:24][C:23]([S:20]([N:7]2[CH2:8][CH2:9][N:10]([C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[O:13])[CH2:11][CH:6]2[C:4]([OH:5])=[O:3])(=[O:22])=[O:21])=[CH:28][CH:27]=1)[C:31]#[C:32][CH3:33]
Reactant: CC#CCOc1ccc(S(=O)(=O)N2CCN(C(=O)N3CCOCC3)CC2C(=O)OCC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC#CCOc1ccc(S(=O)(=O)N2CCN(C(=O)N3CCOCC3)CC2C(=O)O)cc1
Yield: 55.9 %

Procedure:
The 1-(4-but-2-ynyloxy-benzenesulfonyl)-4-(morpholine-4-carbonyl)-piperazine-2-carboxylic acid ethyl ester (0.56 g, 1.18 mmol) was dissolved in THF/MeOH/H2O (3 mL each) and treated with lithium hydroxide monohydrate (0.099 g, 2.3 mmol). The reaction was heated at reflux overnight and then concentrated and acidified to pH 4 with acetic acid. The solution was extracted with methylene chloride and then washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo to provide 0.298 g (53%) of 1-(4-but-2-ynyloxy-benzenesulfonyl)-4-(morpholine-4-carbonyl)- piperazine-2-carboxylic acid as a yellow powder. Electrospray Mass Spec 452.2 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([C:12]#N)=[C:8]([C:10]#[N:11])[N:9]=1)[CH2:2][CH2:3][CH3:4].[C:14]([Mg]Cl)([CH3:17])([CH3:16])[CH3:15].C(OCC)(=[O:22])C.S([O-])(O)(=O)=O.[K+]>C(Cl)Cl.C(OCC)C>[CH2:1]([C:5]1[NH:9][C:8]([C:10]#[N:11])=[C:7]([C:12](=[O:22])[C:14]([CH3:17])([CH3:16])[CH3:15])[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)[Mg]Cl
Reactant: CCOC(C)=O
Reactant: CCCCc1nc(C#N)c(C#N)[nH]1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCc1nc(C(=O)C(C)(C)C)c(C#N)[nH]1
Reaction time: 1 h

Procedure:
A solution of 10.4 g of 2-butylimidazole-4,5-dicarbonitrile (prepared as described in Preparation 1) in 150 ml of methylene chloride was added dropwise in an atmosphere of nitrogen at 10°-15° C. to 100 ml of a 2M solution of t-butylmagnesium chloride in diethyl ether, and the mixture was stirred at the same temperature for 1 hour. 200 ml of ethyl acetate and 100 ml of aqueous potassium hydrogensulfate were then added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 20 minutes. At end of this time, insoluble materials were removed by filtration, and the organic layer was separated, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel, using a 1:3 by volume mixture of ethyl acetate and hexane as the eluent, to give 7.95 g of the title compound as crystals, melting at 135°-137° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([C:19](O)=[O:20])=[C:14]([C:16](=[O:18])[NH2:17])[N:15]=[C:7]3[C:6]=2[CH:22]=1.Cl.[O:24]1[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:10][CH:9]([CH2:12]3)[N:8]3[C:13]([C:19]([NH:30][CH:27]4[CH2:28][CH2:29][O:24][CH2:25][CH2:26]4)=[O:20])=[C:14]([C:16]([NH2:17])=[O:18])[N:15]=[C:7]3[C:6]=2[CH:22]=1
Reactant: NC1CCOCC1
Reactant: NC(=O)c1nc2n(c1C(=O)O)C1CC(C1)c1ccc(Br)cc1-2
Agent: Cl
Product: NC(=O)c1nc2n(c1C(=O)NC1CCOCC1)C1CC(C1)c1ccc(Br)cc1-2

Procedure:
10-bromo-2-carbamoyl-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-3-carboxylic acid (0.1 g) was reacted with tetrahydro-2H-pyran-4-amine hydrochloride similarly to the conditions described in Example 2 to produce 10-bromo-N3-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2,3-dicarboxamide. This intermediate was then reacted with (2R)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol via General Procedure E to afford 5.7 mg (10%) of 10-[(3R)-3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-ynyl]-N3-tetrahydropyran-4-yl-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2,3-dicarboxamide. M+1=516.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[Cl:21][CH:22]([CH:26]=[CH2:27])[C:23](=O)[CH3:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:26]([CH3:27])[CH:22]([Cl:21])[CH:23]=[CH2:24])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: C=CC(Cl)C(C)=O
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Product: C=CC(Cl)C(C)=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1

Procedure:
In the manner given in Example 1, 7-chloro-2-hydrazino -5-phenyl-3H-1,4-benzodiazepine can be reacted with 3-chloro-4-penten-2-one to give 7-chloro-2-[(2-chloro-2 -vinyl-1-methylethylidene)hydrazino]-5-phenyl-3H-1,4-benzodiazepine.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[CH:20](=[O:22])[CH3:21]>C1COCC1.CCOCC>[C:1]1([C:7]#[C:8][CH:20]([OH:22])[CH3:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#Cc1ccccc1
Reactant: CC=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(O)C#Cc1ccccc1
Reaction time: 1 h
Yield: 46.5 %

Procedure:
Phenylacetylene (5.5 mL; 50 mmol) was dissolved in THF (40 mL) and cooled to -78°. A 1.35M solution of n-butyllithium in hexane (37 mL; 50 mmol; 1.0 equiv.) was added dropwise and the resulting mixture was stirred at -78° for 1 h. Acetaldehyde (2.8 mL; 50 mmol; 1.0 equiv.) was added and the reaction mixture was allowed to warm overnight to room temperature. The mixture was diluted with ether (50 mL) and washed with water (3×25 mL). The organic solution was dried (MgSO4) and concentrated, and the crude product was distilled in vacuo, affording 3.4 g (47%) of 1f, bp 94° C./approximately 2 mm Hg. 1H nmr (300 MHz, CDCl3): 7.444-7.261 (5H, m); 4.762 (1H, q, J=5 96 Hz); 1.972 (1H, s); 1.557 (3H, d, J=6.58 Hz). IR (neat film, cm-1): 3400 (s); 1600 (w). FDMS (m/e): 146 (M+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21].CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1.Cl[CH2:45][C:46]1[CH:51]=[CH:50][C:49]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][N:53]=2)=[CH:48][CH:47]=1.BrCC1OC(C(F)(F)F)=CC=1>>[N:53]1[CH:54]=[CH:55][CH:56]=[CH:57][C:52]=1[C:49]1[CH:48]=[CH:47][C:46]([CH2:45][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([CH2:13][O:12][C:11]4[CH:14]=[C:15]5[C:19](=[CH:20][C:10]3=4)[CH2:18][CH2:17][O:16]5)[C:2]2=[O:21])=[CH:51][CH:50]=1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Reactant: ClCc1ccc(-c2ccccn2)cc1
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1N(Cc2ccc(-c3ccccn3)cc2)c2ccccc2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and 2-(4-(chloromethyl)phenyl)pyridine to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 1′-(4-pyridin-2-ylbenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (67%) as a colorless solid: mp 217-219° C.; 1H NMR (300 MHz, CDCl3) δ 8.66 (d, J=4.3 Hz, 1H), 7.96 (d, J=8.0 Hz, 2H), 7.78-7.64 (m, 2H), 7.44 (d, J=8.0 Hz, 2H), 7.25-7.11 (m, 3H), 7.00 (dd, J=7.6, 7.6 Hz, 1H), 6.79 (d, J=7.6 Hz, 1H), 6.49 (s, 1H), 6.42 (s, 1H), 5.00 (ABq, 2H), 4.85 (ABq, 2H), 4.52 (t, J=8.6 Hz, 2H), 3.09-2.87 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.9, 161.7, 161.2, 156.7, 149.6, 141.9, 138.9, 136.7, 136.4, 132.6, 128.6, 127.8, 127.3, 123.8, 123.4, 122.2, 120.4, 120.1, 119.9, 118.8, 109.3, 93.2, 80.6, 72.3, 57.7, 43.8, 29.0; MS (ES+) m/z 447.1 (M+1).
Reaction SMILES: OO.[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][CH:11]([CH3:13])[CH3:12])[C:5]=1[N+:14]([O-:16])=[O:15].C(O)(=[O:19])C.[OH2:21]>>[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10]([CH:11]([CH3:13])[CH3:12])(=[O:19])=[O:21])[C:5]=1[N+:14]([O-:16])=[O:15]
Reactant: CC(=O)O
Reactant: O
Reactant: CC(C)Sc1cccc(F)c1[N+](=O)[O-]
Agent: OO
Product: CC(C)S(=O)(=O)c1cccc(F)c1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
8 M of H2O2 in Water (4.4 mL) was added to a solution of 1-Fluoro-3-isopropylsulfanyl-2-nitro-benzene (6.76 g, 0.031 mol) in Acetic acid (10 mL, 0.2 mol), and the reaction was heated at 100° C. for 16 h HPLC. Addition 2.5 eq H2O2 added. The reaction mixture was cooled and added to ice, when the product precipitated, and was collected by filtration, washed with water and dried under vacuum.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=O)=[CH:4][CH:3]=1.O1CCC[CH2:13]1>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[CH2:13])=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccc(Br)cc21
Reactant: C1CCOC1
Product: C=C1CCc2ccc(Br)cc21
Yield: 93.4 %

Procedure:
6-Bromo-indan-1-one 38b (898 mg, 4.25 mmol) was dissolved in 5 mL of tetrahydrofuran under stirring followed by addition of above mentioned mixture. The reaction mixture was stirred at room temperature for 1 hour prior to quenching by addition of 25 mL of water. The mixture was extracted with dichloromethane (25 mL×4). The combined organic extracts were washed with saturated brine (10 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 6-bromo-1-methylene-indan 38c (830 mg, yield 93.4%) as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:6][CH:5]=[CH:4][N:3]=1.[NH2:18][CH:19]1[CH2:23][CH2:22][NH:21][CH2:20]1>>[NH2:18][CH:19]1[CH2:23][CH2:22][N:21]([C:2]2[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:6][CH:5]=[CH:4][N:3]=2)[CH2:20]1
Reactant: Clc1nccnc1OCCOc1ccccc1
Reactant: NC1CCNC1
Product: NC1CCN(c2nccnc2OCCOc2ccccc2)C1

Procedure:
The title compound was prepared according to the procedure described in Example 4, Step 2, starting from 2-chloro-3-(2-phenoxyethoxy)pyrazine (150 mg, 0.60 mmol; from Example 1, Step 1) and 3-aminopyrrolidine (270 mg, 3.13 mmol) with the exception that a final extraction step between EtOAc and 5% aqueous NaOH was carried out. This gave 121 mg (67%) of the title product. Anal. (C16H19N4O2) C, H; N: calcd, 18.65; found, 18.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C:8]1[S:9][C:10](Br)=[CH:11][N:12]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[Li+].CN(C=O)C.[CH2:22]1COC[CH2:23]1>>[C:1]([O:5][C:6](=[O:14])[NH:7][C:8]1[S:9][C:10]([CH:22]=[CH2:23])=[CH:11][N:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ncc(Br)s1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C=Cc1cnc(NC(=O)OC(C)(C)C)s1

Procedure:
(5-Bromo-thiazol-2-yl)-carbamic acid tert-butyl ester (0.200 g, 0.71 mmol), tetrakis(triphenylphospine)palladium (0.042 g, 0.036 mmol), lithium chloride (0.91 g, 2.14 mmol), and tributyl (vinyl)stannate (0.68 g, 2.14 mmol) were taken in 8 mL of THF and 8 mL of DMF and reflux for 2 hrs. After completion of reaction THF was removed under reduced pressure on ratavapour and the residue was partioned between ethyl acetate (20 mL) and water (20 mL). The layers were separated. Aq. Layer was extracted with ethyl acetate (2×20 mL). The combined organic layer was washed with brine and dried over anhydrous sodium sulfate filtered and concentrated under reduced pressure to get the crude product which was purified by preparative TLC to get the pure product (5-Vinyl-thiazol-2-yl)-carbamic acid tert-butyl ester (0.137 g).
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([CH3:8])[N:7]=1.[CH:10]1([O:16][C:17]2[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[Na+].[Na+].CCOC(C)=O>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:17]1([O:16][C:10]2[CH:15]=[CH:14][C:13]([C:2]3[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([CH3:8])[N:7]=3)=[CH:12][CH:11]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: OB(O)c1ccc(OC2CCCCC2)cc1
Reactant: Cc1cnc(N)c(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Cc1cnc(N)c(-c2ccc(OC3CCCCC3)cc2)n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 52.2 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (55.3 mg) was added to a suspension of 3-bromo-5-methylpyrazin-2-amine (300 mg), 4-(cyclohexyloxy)phenylboronic acid (456 mg) and sodium carbonate (338 mg) in DME (15 mL) and water (3 mL) and the mixture was stirred at 100° C. under nitrogen for 2 hr. Water and EtOAc were added and the organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) and washed with hexane/IPE to give the title compound (236 mg) as a white powder.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[F:6][C:7]([F:23])([F:22])[C:8]([NH:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=1)=[O:9]>O>[CH:19]([C:16]1[CH:17]=[CH:18][C:13]([CH2:12][CH2:11][NH:10][C:8](=[O:9])[C:7]([F:22])([F:23])[F:6])=[C:14]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:15]=1)([CH3:21])[CH3:20]
Reactant: CC(C)c1ccc(CCNC(=O)C(F)(F)F)cc1
Reactant: O=S(=O)(O)Cl
Solvent: O
Product: CC(C)c1ccc(CCNC(=O)C(F)(F)F)c(S(=O)(=O)Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Chlorosulfonic acid (2.05 mL) was added to 1.6 g of 2,2,2-trifluoro-N-[2-(4-isopropylphenyl)ethyl]acetamide, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into ice-water, and water was added to the mixture. The mixture was extracted with ethyl acetate, and the organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate-hexane) to give 0.463 g of 5-isopropyl-2-[2-(2,2,2-trifluoroacetyl-amino)ethyl]benzenesulfonyl chloride.